Human chromosome nondisjunction leads to an extraordinary frequency of aneuploidy: an estimated 10-25% of all human conceptions have too many or too few chromosomes. This chromosome error is the leading cause of pregnancy loss, intellectual disabilities and birth defects. We propose to continue the study of trisomy 21, the cause of Down syndrome (DS), as a model to understand nondisjunction. We have built an unprecedented resource of infants with DS and their parents, including biological samples, epidemiological and clinical data. We have shown that altered recombination patterns along the nondisjoined chromosome are a risk for nondisjunction, and for the first time, have shown that the position of susceptible recombinants differ by the age of the oocyte. Our data have generated new hypotheses that focus on the importance of the genetic architecture of meiotic recombination. We will harness the use of the public genotyping data from genome-wide association studies (GWAS) and our DS repository to gain insight into mechanisms that lead to nondisjunction. First, we will narrow possible mechanism of recombination-based nondisjunction by better understanding recombination patterns in normal meiosis. Second, we will determine the interaction between recombination patterns and environmental and genomic/epigenomic factors that have been associated with nondisjunction, and 3) conduct a GWAS study to identify susceptibility genes for nondisjunction of chromosome 21. Our strategy will ensure progress toward understanding nondisjunction and its consequent impact on the length of woman's reproductive life span. PUBLIC HEALTH RELEVANCE: Human chromosome nondisjunction is the leading cause of pregnancy loss, intellectual disabilities and birth defects. In this competitive renewal, we will focus on uncovering the genetic architecture of meiotic recombination, one important molecular risk factor for nondisjunction. Our strategy to identify recombination-related susceptibility genes will ensure progress toward understanding nondisjunction and its consequent impact on the length of woman's reproductive life span.